Dr. Hajjar is a geriatrician at Hebrew SeniorLife and an Instructor of Medicine at Harvard medical School. The candidate's long-term goal is to become an independent clinical investigator in the area of hypertension and aging by studying the role of the renin angiotensin system (RAS) and its genetics in cognitive and functional impairment and cerebral blood flow changes in the elderly. He will achieve this goal by a proposed career development plan that incorporates: mentorship by Dr. Lewis Lipsitz and a multidisciplinary (geriatrics, hypertension, neuropsychology, biostatistics, genetics, endocrinology, and gerontology) advisory committee;coursework in clinical trials, neurovascular ultrasonography, neuropsychology, and genetic epidemiology;training at neurovasuclar and neuropsychological laboratories;and conduct of a closely mentored patient-oriented research. Recent evidence suggests that RAS plays a role in aging. The candidate has demonstrated in observational studies that treatment with antihypertensives that inhibit RAS may slow down cognitive and functional decline with aging. The environment is academically rich and includes the various organizations and laboratories within the Harvard Medical School which will foster the scientific development and research skills to become an independent researcher. Under the mentorship of Dr. Lipsitz, the research plan is designed to gather preliminary data for future research activities. The first project is to conduct a pilot 3-arm randomized clinical trial of 6-month treatment with an angiotensin receptor blocker, an angiotensin converting enzyme inhibitor (ACEI), and a diuretic in seniors (n=100) with hypertension and objective evidence of early memory loss or executive dysfunction. The outcome measures include cognitive function, physical abilities and cerebral blood flow. The second project is to analyze data from the Health Aging and Body Composition survey to determine if a pharmacogenetic study is justifiable in the future research activities. This analysis will investigate the interaction between angiotensin converting enzyme gene polymorphism and the use of ACEI on cognitive decline in an aging population (n=3,075). Relevance: Findings from this project would provide new treatment modalities for elderly patients suffering from cognitive and physical impairment. It will also allow us to combine expertise from various fields to increase our understanding of the underlying mechanism by which cardiovascular disease affects aging.